This proposal focuses on B cell maturation antigen (BCMA) as a new therapeutic target in antibody-mediated autoimmunity and multiple myeloma (MM). A hallmark of thymus-dependent (TD) immunity is its longevity. One cellular component that contributes to the vast lifespan of humoral immunity is the plasma cell (PC). While PC longevity is an asset for protective humoral immunity, it is a liability in antibody-mediated autoimmunity and in PC malignancies. Preliminary studies show that a newly-identified member of the TNFR family, B cell maturation factor (BCMA) is critical for the survival of long-lived, bone marrow (BM) PCs. This function of BCMA is highly selective, as genetic deletion of BCMA or blocking BCMA appears to influence the survival of terminally-differentiated B cells. Proposed studies are designed to explore how BCMA controls PC longevity and its overall impact on the magnitude and persistence of humoral immunity. Multiple Myeloma (MM) is a malignancy of PCs, typically characterized by the accumulation of PCs within the BM. We will present data that MM cell lines express BCMA and that BCMA might be functionally important in their survival and/or growth. In addition to expressing BCMA, MM cell lines express APRIL, a ligand for BCMA, and thus we may have identified a potential autocrine signaling loop that might be operative in sustaining MM survival and/or growth. Our studies will delineate the expression pattern of BCMA on normal human B cell subsets and on primary MM cells. Functional studies on the role of BCMA in MM survival will be executed using both primary cells and MM cell lines, to delineate how BCMA signaling fosters survival of these cells. The specific aims are: To understand the biological role of BCMA in the survival of plasma cells and its impact on long-lived immunity. To investigate the molecular basis of BlyS/APRIL-BCMA signaling in plasma cells and MM cell lines. To develop BCMA as a therapeutic target in MM.